DPP-IV is a serine protease that recognizes an amino acid sequence having proline (may be alanine, hydroxyproline) at the penultimate position from the N-terminal and produces dipeptide Xaa-Pro (wherein Xaa shows an optional amino acid and Pro shows L-proline). It is known that DPP-IV is widely distributed in the mammalian tissues, particularly in blood, kidney, intestinal epitherlium and placenta.
While the physiological role of DPP-IV in mammal has not been clarified completely, its involvement in a broad range of biological functions such as degradation of neuro-peptide [Heymann et al., FEBS Letters, vol. 91, pp. 360-364 (1978)], activation of T cell [Schon et al., Biomedica Biochimica Acta, vol. 44, pp. K9-K15 (1985)], adhesion of metastatic tumor cells to endothelium [Johnson et al., Journal of Cell Biology, vol. 121, pp. 1423-1432 (1993)], invasion of HIV virus into lymphocyte [Callebaut et al., Science, vol. 262, pp. 2045-2050 (1993)] and the like has been clarified. Of these, the role of DPP-IV as an enzyme that inactivates a biological substance glucagon-like peptide (GLP-1) having a potent insulin secretagogue action, which controls postprandial blood glucose level, has been drawing attention [Deacon et al., Journal of Clinical Endocrinology and Metabolism, vol. 80, pp. 952-957 (1995)].
It is known that GLP-1 is metabolized in several minutes in living organisms. In this respect, metabolism by DPP-V is particularly important, where it rapidly cleaves GLP-1 and produces inactive GLP-1 [Deacon et al., American Journal of Physiology, vol. 271, pp. E458-E464 (1996)]. In addition, since the inactive GLP-1 shows an antagonistic action against GLP-1 receptor, the physiological action of GLP-1 is considered to be further attenuated [Knudsen et al., European Journal of Pharmacology, vol. 318, pp. 429-435 (1996)]. Therefore, a method for suppressing degradation of GLP-1 by DPP-IV inhibition is considered the best approach for enhancing the GLP-1 action, In other words, a DPP-IV inhibitor is expected to be a superior treatment method for correcting postprandial hyperglycemia of non-insulin dependent diabetic (type 2 diabetes) patients, without causing side effects such as prolonged hypoglycemia and the like.
Patent applications relating to DPP-IV inhibitors include the following.
JP-T-9-509921 discloses 1-[N-ε-(hydroxysuccinyl)-L-lysyl]pyrrolidine. This L-lysine moiety is limited to an acyl-substituted form.
JP-T-9-509921 discloses (S)-2-cyano-1-L-prolinepyrrolidine derivative. The L-α-amino acid corresponding to the L-proline moiety of the compound disclosed therein is characterized in that it has a hydrophobic side chain.
In addition, WO99/61431 describes that a compound comprising natural amino acid and thiazolidine or pyrrolidine shows a DPP-IV inhibitory activity.
While many DPP-IV inhibitors have been reported up to the present day [Augustyns et al., Current Medicinal Chemistry, vol. 6, pp. 311-327 (1999)], none of the compounds are sufficient in the inhibitory activity and stability and safety in living organisms, and are not satisfactory as pharmaceutical products. Therefore, the development of a compound having a therapeutic effect based on a DPP-IV inhibitory action and satisfactory as a pharmaceutical product has been desired.